Total Synthesis of Carolacton, a Highly Potent Biofilm Inhibitor

Total Synthesis of Carolacton, a Highly Potent Biofilm Inhibitor

Thomas Schmidt and Andreas Kirschning


Happy new year everybody… I start this year with a nice synthesis from my university done by a very smart student. In this paper a lot of cool metal mediated chemistry is employed which reminds me a bit of the work done by the Fürstner group at the MPI.

Some methodology needs as usual special attention and will be examined at the end of this short write-up.

As the title says Carolacton is a potent biofilm inhibitor which is nowadays a very interesting field to establish new drugs and natural products as biofilms play a major role in clinical treatments.

Retrosynthetically Carolacton was divided in two fragments of almost the same complexity. Beside the crucial macrolactonization step the linear precursor was envisaged to be formed by a stereoselective Nozaki-Hiyama-Kishi reaction. The key steps in the formation of fragment 1 contain an alkyl Negishi coupling and a cool aldol reaction developed by the Ley group. The second fragment was formed among others by a Marshall reaction and an underrepresented Duthaler-Hafner acetate aldol reaction.

Scheme 1

Starting from commercially available lactic acid 3 which was transformed into triflate 4 in a four step sequence through acetylation, ester formation, deacetylation, and triflate formation a zinc mediated SN2 coupling of triflate 4 with homoallyl Grignard formed ester 5. Thorough reduction of the ester group furnished after TIPS protection silyl ether 6. Ozonolysis of the terminal double bond was followed by reductive work-up and Appel reaction to give bromide 7.

Scheme 2

Ester 8, which was obtained by a short protocol developed by Fu et al., was coupled with the corresponding zinc organyl of 7 in the presence of PyBOX-ligand A and a pinch of nickel. Ester 9 is obtained with great diastereoselectivity regarding the red colored methyl group. It was found that it was necessary to grind the added sodium chloride to get good results. [1]

After reduction and manganese dioxide oxidation to aldehyde 10 the above mentioned Ley aldol reaction with ester 15 was employed. Aldol product 11 was obtained in good yield and excellent diastereoselectivity.

Scheme 3

Fragment 15 can easily be prepared through a three step sequence which is shown in detail below. Commercially available diol 12 was first protected as the dioxane ether 13. The 1,2-dimethoxy protecting group is used as a chiral memory unit because the stereochemical information at position 2 is lost during enolization. Chloride elimination and Ozonolysis of the resulting double bond gave after neutral workup ester 15.

Enolization with LHMDS then produces an enolate which reacts in a Zimmermann-Traxler boat conformation transition state with aldehyde 10. The whole story of this methodology can be looked up in the article which is cited above.

Scheme 4

The second half of the synthesis started from propargyl alcohol 16. Oxidation and hydride-transfer reduction with isopropanol catalyzed by Noyori’s catalyst gave enantiomerically pure alcohol 17. Mesylation formed the first partner for the Marshall reaction. The aldehyde partner was obtained from Roche ester 19 which was protected, excessively reduced and again oxidized. Next an anti-selective Marshall reaction mediated by indium(I)iodide and catalyzed by Pd(0) was used to give homo-propargyl alcohol 21. Desilylation with TBAF, acetal formation and chemoselective reduction then furnished after Swern oxidation aldehyde 22. This underwent another interesting reaction: a Duthaler-Hafner titanium mediated aldol reaction with t-butylacetate. This step will be detailed at the end of this post.

After reaction with Meerwein’s salt fragment 2 was almost ready for the Nozaki-Hiyama-Kishi reaction.

Scheme 5

First fragment 11 was freed from the chiral memory unit and the resulting diol protected as the acetonide. During protection the TIPS group was lost and the free alcohol then oxidized to give aldehyde 23.

On the other hand fragment 2 was exposed to Schwartz’s reagent and quenched with iodine to give vinyl iodide 24. In the presence of Cr(II), in situ formed Ni(0), and ligand B both halves were combined to give 25 and 26 as a mixture of diastereomers (~ 1 : 5). [2] Besides carrying the synthesis on with 26, it was tried using the wrong diastereomer 25 in a Mitsunobu process to close the macrolactone. Instead of closing the ring a SN2’ reaction was observed to give the vinylogous macrolactone.

Scheme 6

At last the acyclic precursor 26 was converted into the 12-membered lactone after saponification of the methyl ester and reaction with MNBA. Because of the delicate framework the t-butyl ester was transesterified with TESOTf and desilylated to give 27. PMB removal was followed by Dess-Martin oxidation and acetonide cleavage to yield Carolacton in good yield. [3]

Scheme 7

And as promised here is the mechanistic rationale for the Duthaler-Hafner reaction. Under standard aldol conditions i.e. LDA deprotonation of the acetate and subsequent reaction with aldehyde the diastereoselectivity can be predicted using the Felkin-Anh model. Here the wrong diastereomer is preferred. To overcome this substrate controlled reaction, the enolate is made chiral by using a stoichiometric amount of this furanose modified titanium reagent. After transmetallation of the enolate a Zimmermann-Traxler transition state can be formulated which is inherently controlled by the chiral ligands. This time the correct diastereomer is formed. [4]

Scheme 8

Nice work and worth a read.
[1] Interestingly the Negishi cross coupling can be conducted employing a racemic mixture of the chloride. Only one diastereomer is formed. The authors of this article (DOI: therefore propose a radical pathway.

[2] More about this cool stereoselective Nozaki-Hiyama-Kishi reaction can be found here: DOI:

[3] Interestingly the last deprotection step took 6 days. Pretty tough this acetonide…

[4] If you want to read more about this have a look in here,
Because the paper did not state exactly how the stereochemistry observed can be explained I tried it by myself. If anyone has a better explanation I really would like to hear it.

Total Synthesis of Kapakahine E and F

Total Synthesis of Kapakahine E and F

Vinson R. Espejo and Jon D. Rainier

Two weeks ago this paper catched my eye. Normally I’m not that interested in peptide chemistry but the main part of the paper deals with the construction of the western (red) fragment so it’s almost about C-C-bond chemistry. The red fragment synthesized was then used to build up Kapakahine E and F:

Scheme 1:

From a biological perspective the Kapakahine family members show some potent cytotoxicity against murine leukaemia cells with an in vitro IC50 value of about 5µg/ml. Only one synthesis has been published to date so a second approach might have some potential with regard to analogue synthesis or further biological evaluation.

Scheme 2:

The general idea was to construct the eastern fragment via standard peptide chemistry so the focus of this paper lies on the western half. The tryptophan-dimeric structure was dissected as shown in the scheme so we can start right off with double Boc-protected tryptophan:

Scheme 3:

NBS mediated bromination leads to the formation of the bromo pyrroloindole in high yield but with the wrong configuration of the ester group. Nevertheless the bromine was displaced by indole under conditions developed earlier by the same group (, during which some racemisation occurred. The stereochemistry was then corrected under kinetic deprotonation/reprotonation conditions followed by amide formation with phenylalanine.

Scheme 4:

Global Boc-deprotection and phenylsulfination was followed by a nice AlMe3 mediated ring opening/double ring closing cascade during which dephenylsulfination occurred. The conditions were analogous to this work.

Reductive amination and Fmoc formation completes the scheme.

Scheme 5:

Iodination of the naked indole was accomplished with mercury(II)acetate followed by iodine. The resulting iodoindole was then coupled under modified Negishi conditions with the protected shown zinc-alanine in high yield. Interestingly they needed a stochiometric amount of the ligand and some copper-DMS complex to speed up the reaction rate.

Last but not least to complete the syntheses some peptide chemistry has to be done:

Scheme 6:

The red fragment was debenzylated and coupled with the dipeptide protected as the benzylester. Again debenzylation and ntramolecular lactamisation gave Kapakahine F which was isolated as the triflic acid salt.

Scheme 7:

Kapakahine E was synthesized under the same conditions as utilized for Kapakahine F albeit in lower yield giving this impressive looking molecule.

Nice chemistry; especially the Lewis acid mediated ring closing and the Negishi cross coupling.